Oncology

Combined EGFR/FGFR Inhibitor Therapy Proposed for FGFR2-Positive Intrahepatic Cholangiocarcinoma

Journal Published on December 16, 2022

Originally published on Cancer Discovery

Key findings

Using a series of novel cell lines and xenografts derived from patients with FGFR2 fusion–positive intrahepatic cholangiocarcinoma (ICC), investigators examined which signaling molecules restrict the efficacy of FGFR inhibitor therapy
Feedback activation of EGFR signaling limited the benefit of FGFR inhibitor therapy, restricting cell death induction in models sensitive to FGFR inhibitor monotherapy and causing resistance in insensitive models lacking secondary FGFR2 mutations
The addition of an EGFR inhibitor potentiated the effect of FGFR inhibition in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo
These data support the exploration of dual FGFR/EGFR inhibition as a way to improve initial response rates and extend the benefit to patients with FGFR2+ ICC who have acquired resistance to FGFR inhibitor therapy

Targetable genomic alterations have recently been identified in some patients with intrahepatic cholangiocarcinoma (ICC) who otherwise have few therapeutic options. Fibroblast growth factor receptor 2 (FGFR2) is activated by gene fusions or mutations in about 20% of patients with ICC, and the FGFR inhibitors pemigatinib, infigratinib, and futibatinib are now FDA-approved for that subgroup.

However, despite these precision therapies, some tumors do not respond, disease progression is inevitable, and dose-limiting toxicity is common. Moreover, drug resistance can arise without evidence of acquired genetic alterations.

In preclinical studies, Massachusetts General Hospital researchers have identified feedback activation of the epidermal growth factor receptor as a cause of the modest response rates and emerging resistance to pan-FGFR inhibition. In Cancer Discovery, they present evidence that combined epidermal growth factor receptor (EGFR)/FGFR inhibition may be a therapeutic solution for patients with FGFR2+ ICC.

The authors are Qibiao Wu, PhD, a research fellow at the Mass General Cancer Center, Cyril H. Benes, PhD, principal investigator of the Benes Lab at the Center, Nabeel Bardeesy, PhD, principal investigator of the Bardeesy Lab at the Center, and colleagues.

Models Sensitive to FGFR Inhibition

The researchers studied a series of novel cell lines and xenografts derived from patients with FGFR2 fusion–positive ICC. In models that were highly sensitive to FGFR inhibitor monotherapy:

Monotherapy failed to stimulate pro-apoptotic gene expression or apoptotic cell death in vitro and induced only modest levels in vivo
While FGFR inhibitor monotherapy strongly reduced MEK/ERK phosphorylation, the effect was potentiated by combination FGFR/EGFR inhibition
In vivo, the combination induced an apoptotic gene signature, marked apoptosis, and significant tumor regression

Models Resistant to FGFR Inhibition

The team also studied multiple models that were partially or completely resistant to FGFR inhibitor monotherapy despite lacking FGFR2 kinase domain mutations:

FGFR inhibition suppressed FGFR kinase activity, but there was only minimal or transient reduction in MEK/ERK phosphorylation
FGFR/EGFR inhibition shut down the MEK/ERK pathway and induced apoptotic gene expression and cell death

Secondary Mutations

In most patients with FGFR2+ ICC treated with an FGFR inhibitor, secondary FGFR2 kinase domain mutations emerge at the time of progression. Futibatinib remains active against some of these mutations but not all (Cancer Discovery).

The Mass General team combined futibatinib with afatinib, an EGFR inhibitor approved to treat non–small cell lung cancer, and found:

Compared with futibatinib monotherapy, the combination was better able to reduce viability in ICC cells expressing an FGFR2 fusion harboring the L618V mutation
The N550K mutation was less sensitive to the combination
The V565F mutation was completely refractory

Next-generation FGFR inhibitors are being developed with the goal of greater efficacy against secondary FGFR2 mutations, and they may also improve response to combination therapy.

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Cancer Discovery

Journal Article Published: May 2, 2022

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